1. Field of the Invention
The present invention relates to novel muramyldipeptide derivatives which have excellent adjuvant activity and/or prophylactic and therapeutic effects against microbial infections and, in particular, this invention relates to a muramyldipeptide derivative of the formula (I): ##STR3## wherein X represents an amino acid residue such as of L-alanine, L-serine, L-valine, glycine, etc., and Y represents a group ##STR4## wherein R.sub.1 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a carboxamide group or a carboxyl group, n represents an integer of 1 to 6, A represents a straight or branched chain, saturated or unsaturated aliphatic hydrocarbon residue of 7 to 30 carbon atoms, and "Acyl" means an acyl group of an aliphatic carboxylic acid having 2 to 6 carbon atoms.
That is, the compounds in accordance with the present invention are characterized in that the terminal amino acid group (isoglutamine) is peptide-bonded with an alkylamino group (--NH--A) or an alkyldiamino group in which one of the amino groups is acylated ##STR5##
2. Description of the Prior Art
In recent years, through observations on the developments and prognoses of patients who have fallen into leukemia, malignant lymphocytoma, various carcinomatous diseases or even metabolic insufficiency of the organs, there has been revealed a tendency towards frequent occurrence of microbial infections, especially those complicated with intractable diseases (especially, cases of their agonal infections).
In spite of the development of bacteriological screening, adequate attention to therapeutic activities, improvement of prophylactic techniques against infections and moreover widely spread use of various chemotherapeutic agents, there are deaths resulting from general infections and intractable diseases. Such situation is caused by the injury of the resistant factors against infections, e.g., various phagocytes including polymorphocytes. The injury of the resistant factors is due to not only the reduction in defensive ability of the host against the infection itself but also iatrogenic factors such as antitumor agents, immunosuppressive agents, adrenocortical agents, etc. Accordingly, it has been increasingly sought to develop drugs which have prophylactic and therapeutic effects against the afore-described infections. However, under the present situation that the occurrence of resistant bacteria resulting from frequent use of chemotherapeutic agents and the treatment of infections using weakly toxic bacteria developed by the bacteria exchange phenomenon have become a trouble, there is a great demand for the development of a novel type of drugs which have no direct bactericidal effect and possess prophylactic and therapeutic effects against infections.
There are a few examples hereto known as those exhibiting such actions and effects, i.e., bacterial whole cells, cell wall skeleton, and extracted substances such as lipopolysaccharide or cord factor, which are derived from some species of microorganisms, namely, Mycobacterium, Corynebacterium, Streptococcus, Listeria, and etc. However, these were not permitted to be administered to human because of their side effects such as their own immunogenicity (antigenicity), pyrogenicity, etc.
In addition, it has been reported that N-acetylmuramyl-L-alanyl-D-isoglutamine (hereinafter referred to as "muramyldipeptide") has defensive effect against certain bacterial infections (Proc. Natl. Acad. Sci. USA Vol. 74, No. 5, pp. 2089-2093). However, the effect exhibited by the above compound is not fully satisfactory. Also, PCT WO 79/00802 discloses some muramyldipeptide derivatives but these compounds are different from the compounds of this invention in the structure.